Certain intermediate imino-substituted pyridines

ABSTRACT

Intermediate imino-substituted pyridines of the formula ##STR1## in which R 1  is optionally substituted aryl, 
     R 2  is optionally substituted aryl or alkyl, OH, alkoxy, aralkoxy, or optionally substituted aryloxy, 
     R 3  is isopropyl, 
     R 4  is isopropyl 
     X is --CH 2  --CH 2  -- or --CH═CH--, 
     R is ##STR2## R 6  is H or alkyl, and R 7  is H, alkyl, phenylalkyl, aryl or a cation, and their salts.

This is a division of application Ser. No. 558,029, filed July 26, 1990,now U.S. Pat. No. 5,064,841.

The invention relates to imino-substituted pyridines, to intermediatecompounds for their preparation, and to their preparation and their usein medicaments.

It is known that lactone derivatives isolated from fungal cultures areinhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoAreductase) [mevinolin, EP-A 22,478; US 4,231,938]. In addition,substituted pyridines are described in DOS 3,801,406. Furthermore,3-desmethyl-mevalonic acid derivatives are known (compare DE 3,823,045 A1).

Imino-substituted pyridines of the general formula (I) ##STR3## in which

R¹ represents aryl having 6 to 10 carbon atoms, which is optionallymonosubstituted to trisubstituted by identical or different substituentsfrom the series comprising halogen, hydroxyl, trifluoromethyl,trifluoromethoxy, nitro, cyano, straight-chain or branched alkyl oralkoxy in each case having up to 8 carbon atoms or by aryloxy having 6to 10 carbon atoms,

R² represents aryl having 6 to 10 carbon atoms, which is optionallymonosubstituted to trisubstituted by identical or different substituentsfrom the series comprising straight-chain or branched alkyl in each casehaving up to 8 carbon atoms, halogen, cyano, trifluoromethyl,trifluoromethoxy and nitro, or represents straight-chain or branchedalkyl having up to 10 carbon atoms, which is optionally substituted byaryl having 6 to 10 carbon atoms, hydroxyl or alkoxy having up to 8carbon atoms, or represents a group of the formula --OR⁵, in which

R⁵ denotes hydrogen or straight-chain or branched alkyl having up to 8carbon atoms, which is optionally substituted by aryl having 6 to 10carbon atoms, or denotes aryl having 6 to 10 carbon atoms, which isoptionally substituted by straight-chain or branched alkyl or alkoxy ineach case having up to 8 carbon atoms, halogen, nitro, cyano,trifluoromethyl or trifluoromethoxy,

R³ represents cycloalkyl having 3 to 8 carbon atoms, or represents arylhaving 6 to 10 carbon atoms, which is optionally monosubstituted totrisubstituted by identical or different substituents from the seriescomprising halogen or by straight-chain or branched alkyl having up to 8carbon atoms, or represents straight-chain or branched alkyl having upto 10 carbon atoms, which is optionally substituted by a group of theformula --OR⁵, in which R⁵ has the abovementioned meaning,

R⁴ represents straight-chain or branched alkyl having up to 10 carbonatoms, or represents cycloalkyl, having 3 to 8 carbon atoms,

X represents a group of the formula --CH₂ --CH₂ -- or --CH═CH--, and

R represents a group of the formula ##STR4## in which

R⁶ denotes hydrogen or straight-chain or branched alkyl having up to 10carbon atoms and

R⁷ denotes hydrogen or straight-chain or branched alkyl having up to 10carbon atoms, which may be substituted by phenyl, or denotes aryl having6 to 10 carbon atoms or a cation, and their salts have now been found.

If R⁷ forms an ester radical with the carboxyl group, a physioloqicallytolerable ester radical is preferably meant by this, which is hydroly edeasily in vivo to give a free carboxyl group and an appropriatephysiologically tolerable alcohol. These include, for example, alkylesters (C₁ to C₆) and aralkyl esters (C₇ to C₁₀) preferably (C₁ toC₄)-alkyl esters and benzyl esters. Moreover, the following esterradicals may be mentioned: methyl esters, ethyl esters, propyl estersand benzyl esters.

If R⁷ represents a cation, a physiologically tolerable metal or ammoniumcation is preferably meant. Preferred cations in this connection arealkali metal or alkaline earth metal cations such as, for example,sodium, potassium, magnesium or calcium cations, and also aluminum orammonium cations, and also non-toxic substituted ammonium cations fromamines such as (C₁ -C₄)-dialkylamine, (C₁ -C₄)-trialkylamine, procaine,dibenzylamine, N,N'-dibenzylethylenediamihe,N-benzyl-β-phenylethylamine, N-methylmorpholine or N-ethylmorpholine,1-ephenamine, dihydroabietylamine,N,N'-bis-dihydroabietylethylenediamine, N-loweralkylpiperidine and otheramines which can be used for the formation of salts.

Surprisingly, the imino-substituted pyridines according to the inventionshow a superior inhibitory action on HMG-CoA reductase(3-hydroxy-3-methyl-glutarylcoenzyme A reductase).

Preferred compounds of the general formula (I) are those in which

R¹ represents phenyl which is optionally monosubstituted ordisubstituted by identical or different substituents from the seriescomprising fluorine, chlorine, bromine, hydroxyl, straight-chain orbranched alkyl or alkoxy in each case having up to 6 carbon atoms or byphenoxy,

R² represents phenyl which is optionally monosubstituted ordisubstituted by identical or different substituents from the seriescomprising fluorine, chlorine, bromine or by straight-chain or branchedalkyl having up to 6 carbon atoms, or represents straight-chain orbranched alkyl having up to 8 carbon atoms, which is optionallysubstituted by phenyl or alkoxy having up to 6 carbon atoms, orrepresents a group of the formula --OR⁵ in which

R⁵ denotes hydrogen or straight-chain or branched alkyl having up to 6carbon atoms, which is optionally substituted by phenyl, or denotesphenyl which is optionally substituted by straight-chain or branchedalkyl or alkoxy in each case having up to 6 carbon atoms,

R³ represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, orrepresents phenyl which is optionally monosubstituted or disubstitutedby identical or different substituents from the series comprisingfluorine, chlorine, bromine or by straight-chain or branched alkylhaving up to 6 carbon atoms, or represents straight-chain or branchedalkyl having up to 8 carbon atoms, which is optionally substituted by agroup of the formula --OR⁵ in which

R⁵ has the abovementioned meaning,

R⁴ represents straight-chain or branched alkyl having up to 8 carbonatoms, or represents cyclopropyl, cyclopentyl or cyclohexyl,

X represents a group of the formula --CH₂ --CH₂ -- or --CH═CH-- and

R represents a group of the formula ##STR5## in which

R⁶ denotes hydrogen or straight-chain or branched alkyl having up to 8carbon atoms and

R⁷ denotes hydrogen or straight-chain or branched alkyl having up to 8carbon atoms or benzyl, or denotes phenyl or a cation, and their salts.

Particularly preferred compounds of the general formula (I) are those inwhich

R¹ represents phenyl which is optionally substituted by fluorine,chlorine, straight-chain or branched alkyl having up to 4 carbon atomsor phenoxy, or

R² represents a group of the formula --OR⁵ in which

R⁵ denotes hydrogen, benzyl or straight-chain or branched alkyl havingup to 4 carbon atoms or denotes phenyl,

R³ represents cyclopropyl or phenyl, or represents straight-chain orbranched alkyl having up to 6 carbon atoms, which is optionallysubstituted by a group of the formula --OR⁵ in which

R⁵ has the abovementioned meaning,

R⁴ represents straight-chain or branched alkyl having up to 6 carbonatoms or cyclopropyl,

X represents a group --CH═CH-- and

R represents a group of the formula ##STR6## in which

R⁶ denotes hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutylor tert.butyl and

R⁷ denotes hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert.butyl or benzyl, or denotes a sodium, potassium, calcium, magnesiumor ammonium ion, and their salts.

R⁶ particularly preferably represents hydrogen.

The imino-substituted pyridines of the general formula (I) according tothe invention have several asymmetric carbon atoms and can thereforeexist in various stereochemical forms. The invention relates to both theindividual isomers and to their mixtures.

Depending on the meaning of the group X or the radical R, differentstereoisomers are formed, which are illustrated in more detail in thefollowing:

a) If the group --X-- represents a group of the formula --CH═CH--, thecompounds according to the invention can exist in two stereoisomericforms which can have the E-configuration (II) or the Z-configuration(III) of the double bond: ##STR7## (R¹, R², R³ and R⁴ have theabovementioned meanings).

Preferred compounds of the general formula (I) are those which have theE-configuration (II).

b) If the radical --R represents a group of the formula ##STR8## thenthe compounds of the general formula (I) have at least two asymmetriccarbon atoms, namely the two carbon atoms to which the hydroxyl groupsare bonded. Depending on the relative position of these hydroxyl groupsto one another, the compounds according to the invention can be in theerythro-configuration (IV) or the threoconfiguration (V). ##STR9##

In each case, two enantiomers in turn exist of both the compounds in theerythro- and the threoconfiguration, namely the 3R,5S-isomer or the3S,5R-isomer (erythro form) and the 3R,5R-isomer and the 3S,5S-isomer(threo form).

The isomers in the erythro-confiquration are preferred in this case,particularly preferably the 3R,5S-isomer and the 3R,5S-3S,5R-racemate.

c) If the radical --R represents a group of the formula ##STR10## thenthe imino-substituted pyridines have at least two asymmetric carbonatoms, namely the carbon atom to which the hydroxyl group is bonded, andthe carbon atom to which the radical of the formula ##STR11## is bonded.Depending on the position of the hydroxyl group to the free valency onthe lactone ring, the iminosubstituted pyridines can be present ascis-lactones (VI) or as trans-lactones (VII). ##STR12##

In each case, two isomers in turn exist of both the cis-lactone and thetrans-lactone, namely the 4R,6R-isomer or the 4S,6S-isomer(cis-lactone), and the 4R,6S-isomer or 4S,6R-isomer (trans-lactone). Thetrans-lactones are the preferred isomers. The 4R,6S-isomer (trans) andthe 4R,6S-4S,6R-racemate is particularly preferred in this connection.

For example, the following isomeric forms of the imino-substitutedpyridines may be mentioned: ##STR13##

In addition, a process for the preparation of the imino-substitutedpyridines of the general formula (I) ##STR14## in which

R¹, R², R³, R⁴, X and R have the abovementioned meanings has been found,which is characterized in that ketones of the general formula (VIII)##STR15## in which

R¹, R², R³, R⁴, X and R have the abovementioned meanings and

R⁸ represents alkyl, are reduced, in the case of the preparation of theacids, the esters are hydrolyzed, in the case of the preparation of thelactones, the carboxylic acids are cyclized, in the case of thepreparation of the salts, either the esters or the lactones arehydrolyzed, in the case of the preparation of the ethylene compounds(X═--CH₂ --CH₂ --), the ethene compounds (X=--CH═CH₋₋) are hydrogenatedby customary methods, and, if appropriate, isomers are separated.

The process according to the invention can be illustrated by thefollowing equation: ##STR16##

The reduction can be carried out using the customary reducing agents,preferably using those which are suitable for the reduction of ketonesto hydroxyl compounds. In this case, reduction with metal hydrides orcomplex metal hydrides in inert solvents, if appropriate in the presenceof a trialkylborane, is particularly suitable. Reduction is preferablycarried out using complex metal hydrides such as, for example, lithiumborohydride, sodium borohydride, potassium borohydride, zincborohydride, lithium trialkylborohydrides, sodium trialkylborohydrides,sodium cyanoborohydrides or lithium aluminium hydride. Very particularlypreferably, reduction is carried out using sodium borohydride in thepresence of triethylborane.

Suitable solvents in this connection are the customary organic solventswhich do not change under the reaction conditions. These preferablyinclude ethers such as, for example, diethyl ether, dioxane,tetrahydrofuran or dimethoxyethane, or halogenated hydrocarbons such as,for example, dichloromethane, trichloromethane, tetrachloromethane,1,2-dichloroethane, or hydrocarbons such as, for example, benzene,toluene or xylene. It is also possible to use mixtures of the solventsmentioned.

The reduction of the ketone group to the hydroxyl group is particularlypreferably carried out under conditions in which the other functionalgroups such as, for example, the alkoxycarbonyl group, are not changed.The use of sodium borohydride as a reducing agent, in the presence oftriethylborane in inert solvents such as, preferably, ethers, isparticularly suitable for this.

The reduction is in general carried out in a temperature range from -80°C. to +30° C., preferably from -78° C. to 0° C.

The reduction is in general carried out at normal pressure. However, itis also possible to carry out the process at reduced pressure or atelevated pressure (for example in a range from 0.5 to 5 bar).

In general, the reducing agent is employed in an amount of 1 to 2 moles,preferably 1 to 1.5 moles relative to 1 mole of the ketone compound.

Under the abovementioned reaction conditions, the carbonyl group is ingeneral reduced to the hydroxyl group without reduction of the doublebond to a single bond taking place.

In order to prepare compounds of the general formula (I) in which Xrepresents an ethylene group, the reduction of the ketones (VIII) can becarried out under those conditions in which both the carbonyl group andthe double bond are reduced

Moreover, it is also possible to carry out the reduction of the carbonylgroup and the reduction of the double bond in two separate steps.

The carboxylic acids in the context of the general formula (I)correspond to the formula (Ic) ##STR17## in which

R¹, R², R³, R⁴, R⁶ and X have the abovementioned meanings,

The carboxylic acid esters in the context of the general formula (I)correspond to the formula (Id) ##STR18## in which

R¹, R², R³, R⁴, R⁶, R⁸ and X have the abovementioned meanings.

The salts of the compounds according to the invention in the context ofthe general formula (I) correspond to the formula (Ie) ##STR19## inwhich

R¹, R², R³, R⁴, R⁶ and X have the abovementioned meanings, and

M^(n+) represents a cation, where n indicates the valency.

The lactones in the context of the general formula (I) correspond to theformula (If) ##STR20## in which

R¹, R², R³, R⁴, R⁶ and X have the abovementioned meanings.

In order to prepare the carboxylic acids of the general formula (Ic)according to the invention, the carboxylic esters of the general formula(Id) or the lactones of the general formula (If) are in generalhydrolyzed by customary methods. The hydrolysis is in general carriedout by treating the esters or the lactones with customary bases in inertsolvents, the salts of the general formula (Ie) in general being formedfirst, and it then being possible to convert these into the free acidsof the general formula (Ic) in a second step by treating with acid.

Suitable bases for the hydrolysis are the customary inorganic bases.These preferably include alkali metal hydroxides or alkaline earth metalhydroxides such as, for example, sodium hydroxide, potassium hydroxideor barium hydroxide, or alkali metal carbonates such as sodium carbonateor potassium carbonate or sodium hydrogen carbonate, or alkali metalalkoxides such as sodium ethoxide, sodium methoxide, potassiummethoxide, potassium ethoxide or potassium tert.butoxide. Sodiumhydroxide or potassium hydroxide are particularly preferably employed.

Suitable solvents for the hydrolysis are water or the organic solventscustomary for hydrolysis. These preferably include alcohols such asmethanol, ethanol, propanol, isopropanol or butanol, or ethers such astetrahydrofuran or dioxane, or dimethylformamide or dimethyl sulphoxide.Alcohols such as methanol, ethanol, propanol or isopropanol areparticularly preferably used. It is also possible to use mixtures of thesolvents mentioned.

The hydrolysis is in general carried out in a temperature range of 0° C.to +100° C., preferably +20° C. to 80° C.

In general, the hydrolysis is carried out at normal pressure. However,it is also possible to work at reduced pressure or at elevated pressure(for example from 0.5 to 5 bar).

When carrying out the hydrolysis, the base is in general employed in anamount of 1 to 3 moles, preferably 1 to 1.5 moles, relative to 1 mole ofthe ester or the lactone. Molar amounts of the reactants areparticularly preferably used.

When carrying out the hydrolysis, the salts of the compounds (Ie)according to the invention are formed in the first step as intermediateswhich can be isolated. The acids (Ic) according to the invention areobtained by treating the salts (Ie) with customary inorganic acids.These preferably include mineral acids such as, for example,hydrochloric acid, hydrobromic acid, sulphuric acid or phosphoric acid.In this case, it has proved advantageous in the preparation of thecarboxylic acids (Ic) to acidify the basic reaction mixture from thehydrolysis in a second step without isolation of the salts. The acidscan then be isolated in a customary manner.

In order to prepare the lactones of the formula (If) according to theinvention, the carboxylic acids (Ic) according to the invention are ingeneral cyclized by customary methods, for example by heating thecorresponding acid in inert organic solvents, if appropriate in thepresence of molecular sieve.

Suitable solvents for the cyclization are hydrocarbons such as benzene,toluene, xylene, mineral oil fractions, or tetralin or diglyme ortriglyme. Benzene, toluene or xylene are preferably employed It is alsopossible to employ mixtures of the solvents mentioned. Particularlypreferably, hydrocarbons, in particular toluene, are used in thepresence of molecular sieve.

The cyclization is in general carried out in a temperature range of -40°C. to +200° C., preferably -25° C. to +50° C.

The cyclization is in general carried out at normal pressure, but it isalso possible to carry out the process at reduced pressure or atelevated pressure (for example in a range from 0.5 to 5 bar).

Moreover, the cyclization is also carried out in inert organic solvents,with the aid of cyclizing or dehydrating agents. Dehydrating agents usedin this connection are preferably carbodiimides. Carbodiimides employedare preferably N,N'-dicyclohexylcarbodiimide paratoluenesulphonate,N-cyclohexyl-N'-[2-(N"-methylmorpholinium)ethyl]carbodiimide orN-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride.

Suitable solvents in this connection are the customary organic solventsThese preferably include ethers such as diethyl ether, tetrahydrofuranor dioxane, or chlorinated hydrocarbons such as methylene chloride,chloroform or carbon tetrachloride, or hydrocarbons such as benzene,toluene, xylene or mineral oil fractions. Chlorinated hydrocarbons suchas, for example, methylene chloride, chloroform or carbon tetrachloride,or hydrocarbons such as benzene, toluene, xylene, or mineral oilfractions are particularly preferred. Chlorinated hydrocarbons such as,for example, methylene chloride, chloroform or carbon tetrachloride arevery particularly preferably employed.

The cyclization is in general carried out in a temperature range of 0°C. to +80° C., preferably +10° C. to +50° C.

When carrying out the cyclization, it has proved advantageous to employthe cyclization methods using carbodiimides as dehydrating agents.

The separation of the isomers into the stereoisomerically uniformconstituents is in general carried out by customary methods such as aredescribed, for example, by E. L. Eliel, Stereochemistry of CarbonCompounds, McGraw Hill, 1962. The separation of the isomers in theracemic ester step is preferred in this connection. Particularlypreferably, the racemic mixture of the trans lactones (VII) is in thiscase converted by treating either with D-(+)- orL-(-)-α-methylbenzylamine by customary methods into the diastereomericdihydroxyamides (Ig) ##STR21## which can subsequently be separated, asis customary, into the individual diastereomers by chromatography orcrystallization. Subsequent hydrolysis of the pure diastereomeric amidesby customary methods, for example by treating the diastereomeric amideswith inorganic bases such as sodium hydroxide or potassium hydroxide inwater and/or organic solvents such as alcohols, for example methanol,ethanol, propanol or isopropanol, gives the correspondingenantiomerically pure dihydroxy acids (Ic), which can be converted intothe enantiomerically pure lactones by cyclization as described above. Ingeneral, it holds true for the preparation of the compounds of thegeneral formula (I) according to the invention in enantiomerically pureform that the configuration of the final products according to themethod described above is dependent on the configuration of the startingmaterials.

The separation of isomers is intended to be illustrated by way ofexample in the following scheme: ##STR22##

The ketones (VIII) employed as starting materials are new.

A process for the preparation of the ketones of the general formula(VIII) according to the invention ##STR23## in which

R¹, R², R³ and R⁸ have the abovementioned meanings, has been found,which is characterized in that aldehydes of the general formula (IX)##STR24## in which

R¹, R², R³ and R⁴ have the abovementioned meanings, are reacted in inertsolvents with acetoacetic acid esters of the general formula (X)##STR25## in which

R⁸ has the abovementioned meaning, in the presence of bases.

The process according to the invention can be illustrated, for example,by the following equation: ##STR26##

Suitable bases in this connection are the customary strongly basiccompounds. These preferably include organolithium compounds such as, forexample, n-butyllithium, sec.butyllithium, tert.butyllithium orphenyllithium, or amides, such as, for example, lithiumdiisopropylamide, sodium amide or potassium amide, or lithiumhexamethyldisilylamide, or alkali metal hydrides such as sodium hydrideor potassium hydride. It is also possible to employ mixtures of thebases mentioned. n-butyllithium or sodium hydride or a mixture thereofis particularly preferably employed.

Additions of metal halides, such as, for example, magnesium chloride,zinc chloride or zinc bromide may be advantageous. The addition of zinchalides is particularly preferable.

Suitable solvents in this connection are the customary organic solventswhich do not change under the reaction conditions. These preferablyinclude ethers such as diethyl ether, tetrahydrofuran, dioxane ordimethoxyethane, or hydrocarbons such as benzene, toluene, xylene,cyclohexane, hexane or mineral oil fractions. It is also possible toemploy mixtures of the solvents mentioned. Ethers such as diethyl etheror tetrahydrofuran are particularly preferably used.

The reaction is in general carried out in a temperature range of -80° C.to +50° C., preferably -20° C. to room temperature.

The process is in general carried out at normal pressure, but it is alsopossible to carry out the process at reduced pressure or at elevatedpressure, for example in a range from 0.5 to 5 bar.

When carrying out the process, the acetoacetic acid ester is in generalemployed in an amount of 1 to 2, preferably 1 to 1.5 moles, relative to1 mole of the aldehyde.

The acetoacetic acid esters of the formula (X) employed as startingmaterials are known or can be prepared by known methods [Beilstein'sHandbuch der organischen Chemie (Beilstein's Handbook of OrganicChemistry) III, 632; 438].

Examples of acetoacetic acid esters which may be mentioned for theprocess according to the invention are: methyl acetoacetate, ethylacetoacetate, propyl acetoacetate and isopropyl acetoacetate.

The preparation of the aldehydes of the general formula (IX) employed asstarting materials is intended to be illustrated by way of example inthe following scheme [A]. ##STR27##

In this connection, the imino-substituted pyridines of the formula (XI),in which R⁹ represents a typical hydroxyl protecting group, for examplethe tert.butyldimethylsilyl radical, are converted into thehydroxymethyl compounds (XII) in the first step [1] in inert solventssuch as ether, for example diethyl ether, tetrahydrofuran or dioxane,preferably tetrahydrofuran, with removal of the radical R⁹ by acustomary method, for example using tetrabutylammonium fluoride. Thereaction proceeds in a temperature range of -10° C. to +60° C.,preferably at 0° C. to +30° C.

The hydroxymethyl compounds (XII) are oxidized to the aldehydes (XIII)by customary methods in the second step [2]. The oxidation can becarried out, for example, using pyridinium chlorochromate, ifappropriate in the presence of alumina, in inert solvents such aschlorinated hydrocarbons, preferably methylene chloride, in atemperature range of 0° C. to 60° C., preferably at room temperature, orelse using trifluoroacetic acid/dimethyl sulphoxide according to thecustomary methods of the Swern oxidation. The aldehydes (XIII) arereacted to give the aldehydes (IX) in the third step [3] using diethyl2-(cyclohexylamino)-vinylphosphonate in the presence of sodium hydridein inert solvents such as ethers, for example diethyl ether,tetrahydrofuran or dioxane, preferably in tetrahydrofuran, in atemperature range of -20° C. to +40° C., preferably -5° C. to roomtemperature.

The substituted pyridines of the formula (XI) employed as startingmaterials are new. They are obtained in general according to scheme [B],by a process in which

[B] Compounds of the general formula (XIV) ##STR28## in which

R¹, R³, R⁴ and R⁹ have the abovementioned meanings, are reacted withamines or hydroxylamine derivatives of the general formula (XV)

    H.sub.2 N--R.sup.2                                         (XV)

in which

R² has the abovementioned meaning, in one of the abovementionedsolvents, preferably methylene chloride, in a temperature range of 0° C.to +70° C., preferably at room temperature.

The compounds of the general formula (XIV) are known per se or can beprepared by a known method (compare DOS 3,801,406).

The compounds of the general formula (XV) are also known (compareBeilstein 1, 288, Houben-Weyl's "Methoden der organischen Chemie"(Methods of Organic Chemistry), vol. XII 1 and XII 2).

The compounds of the general formula (I) according to the invention haveuseful pharmacological properties and can be employed in medicaments Inparticular, they are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A(HMG-CoA) reductase and, as a result, inhibitors of cholesterolbiosynthesis. They can therefore be employed for the treatment ofhyperlipoproteinaemia, lipoproteinaemia or atherosclerosis. The activecompounds according to the invention additionally cause a lowering ofthe cholesterol content in the blood.

The enzyme activity determination was carried out as modified by G. C.Ness et al., Archives of Biochemistry and Biophysics 197, 493-499(1979). Male Rico rats (body weight 300-400 g) were treated withaltromin powdered feed, to which 40 g of cholestyramine/kg of feed hadbeen added, for 11 days. After decapitation, the livers were removedfrom the animals and placed on ice. The livers were comminuted andhomogenized three times in a Potter-Elvejem homogenizer in 3 volumes of0.1 M sucrose, 0.05 M KCl, 0.04 M K_(x) H_(y) phosphate, 0.03 Methylenediaminetetraacetic acid, 0.002 M dithiothreitol (SPE) buffer pH7.2. The mixture was then centrifuged at 15,000 g for 15 minutes and thesediment was discarded. The supernatant was sedimented at 100,000 g for75 minutes. The pellet is taken up in 1/4 volume of SPE buffer,homogenized again and then centrifuged again at 100,000 g for 60minutes. The pellet is taken up using a 5-fold amount of its volume ofSPE buffer, homogenized and frozen and stored at -78° C. (=enzymesolution).

For testing, the test compounds (or mevinolin as a reference substance)were dissolved in dimethylformamide with the addition of 5 vol.-% of 1 NNaOH and employed in the enzyme test using 10 μl in variousconcentrations. The test was begun after 20 minutes preincubation of thecompounds with the enzyme at 37° C. The test mixture amounted to 0.380ml and contained 4 μmol of glucose 6-phosphate, 1.1 mg of bovine serumalbumin, 2.1 μmol of dithiothreitol, 0.35 μmol of NADP, 1 unit ofglucose 6-phosphate dehydrogenase, 35 μmol of K_(x) H_(y) phosphate pH7.2, 20 μl of enzyme preparation and 56 nmol of3-hydroxy-3-methyl-glutaryl coenzyme A (glutaryl-3-¹⁴ C) of 100,000 dpm.

After an incubation of 60 minutes at 37° C., the mixture was centrifugedand 600 μl of the supernatant was applied to a 0.7×4 cm column packedwith a 5-chloride 100-200 mesh (anion exchanger). The column was washedwith 2 ml of distilled water and 3 ml of Aquasol was added to therunning plus washing water and counted in an LKB scintillation counter.IC₅₀ values were determined by intrapolation by plotting the percentageinhibition against the concentration of the compound in the test. Inorder to determine the relative inhibitory potency, the IC₅₀ value ofthe reference substance mevinolin was set at 1 and compared with thesimultaneously determined IC₅₀ value of the test compound.

The new active compounds can be converted in a known manner into thecustomary formulations, such as tablets, coated tablets, pills,granules, aerosols, syrups, emulsions, suspensions and solutions, usinginert, non-toxic, pharmaceutically suitable excipients or solvents. Inthis connection, the therapeutically active compound should in each casebe present in a concentration of about 0.5 to 98% by weight, preferably1 to 90% by weight, of the total mixture, i.e. in amounts which aresufficient in order to achieve the dosage range indicated.

The formulations are prepared, for example, by extending the activecompounds with solvents and/or excipients, if appropriate usingemulsifiers and/or dispersants, it being possible, for example, in thecase of the use of water as a diluent, to use, if appropriate, organicsolvents as auxiliary solvents.

Examples of auxiliary solvents which may be mentioned are: water,non-toxic organic solvents, such as paraffins (for example mineral oilfractions), vegetable oils (for example ground nut/sesame oil), alcohols(for example: ethylalcohol, glycerol), excipients, such as, for example,ground natural minerals (for example, kaolins, aluminas, talc, chalk),ground synthetic minerals (for example highly disperse silica,silicates), sugars (for example sucrose, lactose and dextrose),emulsifiers (for example polyoxyethylene fatty acid esters,polyoxyethylene fatty alcohol ethers, alkylsulphonates andarylsulphonates), dispersing agents (for example lignin-sulphite wasteliquors, methylcellulose, starch and polyvinylpyrrolidone) andlubricants (for example magnesium stearate, talc, stearic acid andsodium laurylsulphate).

Administration is carried out in a customary manner, preferably orally,parenterally, perlingually or intravenously. In the case of oraladministration, tablets can of course also contain additions, such assodium citrate, calcium carbonate and dicalcium phosphate together withvarious additives, such as starch, preferably potato starch, gelatin andthe like in addition to the excipients mentioned. Furthermore,lubricants, such as magnesium stearate, sodium laurylsulphate and talccan additionally be used for tabletting. In the case of aqueoussuspensions, various flavor enhancers or colorants may be added to theactive compounds in addition to the abovementioned auxiliaries.

In the case of parenteral administration, solutions of the activecompounds can be employed using suitable liquid excipient materials.

In general, it has proved advantageous on intravenous administration toadminister amounts of about 0.001 to 1 mg/kg, preferably about 0.01 to0.5 mg/kg of body weight to attain effective results, on oraladministration the dosage is about 0.01 to 20 mg/kg, preferably 0.1 to10 mg/kg of body weight.

In spite of this it may be necessary to deviate from the amountsmentioned, depending in particular on the body weight or the manner ofadministration, on individual behavior towards the medicament, themanner of its formulation and the point in time or interval at whichadministration takes place.

Thus, in some cases it may be sufficient to manage with less than theminimum amount previously mentioned, while in other cases the upperlimit mentioned must be exceeded In the case of the administration ofrelatively large amounts, it may be advisable to divide these into anumber of individual doses over the course of the day.

STARTING COMPOUNDS Example I(E/Z)-4-carboxyethyl-5-(4-fluorophenyl)-2-methyl-pent-4-en-3-one##STR29##

62 g (0.5 mol) of 4-fluorobenzaldehyde and 79 g (0.5 mol) of ethylisobutyrylacetate are initially introduced into 300 ml of isopropanoland a mixture of 2.81 ml (28 mmol) of piperidine and 166 ml (29 mmol) ofacetic acid in 40 ml of isopropanol is added. The mixture is stirred atroom temperature for 48 hours, concentrated in vacuo and the residue isdistilled in a high vacuum.

B.p. 0.5 mm; 127° C.

Yield: 108.7 g (82.3% of theory).

Example II Diethyl1,4-dihydro-2,6-diisopropyl-4-(4-fluorophenyl)pyridine-3,5-dicarboxylate##STR30##

98 g (0.371 mol) of the compound from Example I are heated to reflux for18 h with 58.3 g (0.371 mol) of ethyl 3-amino-4methyl-pent-2-enoate in300 ml. of ethanol. The mixture is cooled to room temperature, thesolvent is evaporated in vacuo and the unreacted starting materials areremoved by distillation in a high vacuum at 130° C. The remaining syrupis stirred with n-hexane and the deposited precipitate is filtered offwith suction, washed with n-hexane and dried in a desiccator.

Yield: 35 g (23.4% of theory).

¹ H NMR (CDCl₃): δ=1.1-1.3 (m, 18H); 4.05-4.25 (m, 6H); 5.0 (s, 1H);6.13 (s, 1H); 6.88 (m, 2H); 7.2 (m, 2H) ppm.

Example III Diethyl2,6-diisopropyl-4-(4-fluorophenyl)-pyridine-3,5-dicarboxylate ##STR31##

3.8 g (16.4 mmol) of 2,3-dichloro-5,6-dicyano-p-benzoquinone are addedto a solution of 6.6 g (16.4 mmol) of the compound from Example II in200 ml of methylene chloride p.A. and the mixture is stirred at roomtemperature for 1 hour. It is then filtered through kieselguhr withsuction, and the methylene chloride phase is extracted 3 times with 100ml of water each time and dried over magnesium sulphate. Afterconcentrating in vacuo, the residue is chromatographed on a column (100g of silica gel 70-230 mesh, φ 3.5 cm, using ethyl acetate/petroleumether 1:9)

Yield: 5.8 g (87.9% of theory)

¹ H NMR (CDCl₃): δ=0.98 (t, 6H); 1.41 (d, 12H); 3.1 (m, 2H}; 4.11 (q,4H); 7.04 (m, 2H); 7.25 (m, 2H) ppm.

Example IV Ethyl2,6-diisopropyl-4-(4-fluorophenyl)-5-hydroxymethyl-pyridine-3-carboxylate##STR32##

21 ml (80.5 mmol) of a 3.5 molar solution of sodium bis-(2-methoxyethoxy)-dihydroaluminate in toluene are added at -10° C. to -5° C. undernitrogen to a solution of 9.2 g (23 mmol) of the compound from ExampleIII in 100 ml of dry tetrahydrofuran and the mixture is stirred at roomtemperature for 5 h. After cooling to 0° C., 100 ml of water arecautiously added dropwise and the mixture is extracted 3 times with 100ml of ethyl acetate each time. The combined organic phases are washedwith saturated sodium chloride solution, dried over magnesium sulphateand concentrated in vacuo. The residue is chromatographed on a column(200 g of silica gel 70-230 mesh, φ 4.5 cm, using ethylacetate/petroleum ether 3:7).

Yield: 7.2 g (87.2% of theory)

¹ H NMR (CDCl₃): δ=0.95 (t, 3H); 1.31 (m, 12H); 3.05 (m, 1H); 3.48 (m,1H), 3.95 (q, 2H); 4.93 (d, 2H); 7.05-7.31 (m, 4H) ppm.

Example V Ethyl 5-(tertbutyldimethylsilyloxymethyl)-2,6-diisopropyl-4-(4-fluorophenyl)-pyridine-3-carboxylate##STR33##

2.1 g (13.8 mmol) of tert butyldimethylsilyl chloride, 1.8 g (27.5 mmol)of imidazole and 0.05 g of 4-dimethylaminopyridine are added at roomtemperature to a solution of 4.5 g (12.5 mmol) of the compound fromExample IV in 50 ml of dimethylformamide. The mixture is stirredovernight at room temperature, 200 ml of water are added and it isadjusted to pH 3 with N hydrochloric acid. The mixture is extractedthree times with 100 ml of ether each time, and the combined organicphases are washed once with saturated sodium chloride solution, driedover magnesium sulphate and concentrated in vacuo. The residue ischromatographed on a column (150 g of silica gel, 70-230 mesh, φ 4 cm,using ethyl acetate/petroleum ether 1:9).

Yield: 4.2 g (73.7% of theory)

¹ H NMR (CDCl₃): δ=0.0 (s, 6H); 0.9 (s, 9H); 1.02 (t, 3H); 1.35 (m,12H); 3.1 (m, 1H); 3.47 (m, 1H); 4.03 (q, 2H); 4.4 (s, 2H); 7.05-7.40(m, 4H) ppm.

Example VI3-(tert.Butyldimethylsilyloxymethyl)-2,6-diisopropyl-4-(4-fluorophenyl)-5-hydroxymethyl-pyridine##STR34##

9.2 ml (32.2 mmol) of a 3.5 molar solution of sodiumbis-(2-methoxyethoxy)-dihydroaluminate in toluene are added at 0° C.under nitrogen to a solution of 4.2 g (9.2 mmol) of the compound fromExample V in 100 ml of dry tetrahydrofuran and the mixture is stirredovernight at room temperature. After cooling to 0° C., 100 ml of waterare cautiously added dropwise and the mixture is extracted 3 times with100 ml of ethyl acetate each time. The combined organic phases arewashed once with saturated sodium chloride solution, dried overmagnesium sulphate and concentrated in vacuo. The residue ischromatographed on a column (100 g of silica gel 70-230 mesh, φ 3.5 cm,using ethyl acetate/petroleum ether 2:8).

Yield: 2.4 g (60% of theory).

¹ H NMR (CDCl₃): δ=0.2 (s, 6H); 1.11 (s, 9H); 1.6 (m, 12H); 3.7 (m, 2H);4.55 (s, 2H); 4.65 (d, 2H); 7.35-7.55 (m, 4H) ppm.

Example VII5-(tert.Butyldimethylsilyloxymethyl)-2,6-diisopropyl)-4-(4-fluorophenyl)-pyridine-3-carbaldehyde##STR35##

1.24 g (12.4 mmol) of neutral alumina and 2.7 g (12.4 mmol) ofpyridinium chlorochromate are added to a solution of 2.7 g (6.2 mmol) ofthe compound from Example VI in 50 ml of methylene chloride and themixture is stirred at room temperature for 1 hour. The solution isfiltered with suction through kieselguhr, which is then washed with 200ml of methylene chloride. The methylene chloride phase is concentratedin vacuo and the residue is chromatographed on a column (100 g of silicagel 70-230 mesh, φ 3.5 cm, using ethyl acetate/petroleum ether 1:9).

Yield: 2 g (77% of theory).

¹ H NMR (CDCl₃): δ=0.0 (s, 6H); 0.9 (s, 9H); 1.35 (m, 12H); 3.5 (m, 1H);3.9 (m, 1H); 4.38 (s, 2H); 7.15-7.35 (m, 4H); 9.8 (s, 1H) ppm.

PREPARATION EXAMPLES Example 13-(tert.-Butyldimethylsilyloxymethyl)-2,6-diisopropyl-4-(4-fluorophenyl)5-methoxyiminomethyl-pyridine##STR36##

626 mg (7.5 mmol) of 0-methylhydroxylamine hydrochloride and 0.6 ml (7.5mmol) of pyridine are added to a solution of 2.1 g (5 mmol) of thecompound from Example VII in 50 ml of ethanol p.A. and the mixture isheated under reflux for 1 hour. After cooling to room temperature, it isconcentrated to one half on a rotary evaporator. The crystals whichdeposit on further cooling to 0° C. are filtered off with suction anddried.

Yield: 1.52 g (66.4 % of theory).

¹ H NMR (CDCl₃): δ=0.01 (s, 6H); 0.91 (s, 9H); 1.48 (m, 2H); 3.50 (sept.1H); 3.68 (sept. 1H); 3.89 (s, 3H); 4.39 (s, 2H); 7.10-7.30 (m, 4H);7.82 (s, 1H) ppm.

Example 22,6-Diisopropyl-4-(4-fluorophenyl)-3-hydroxymethyl-5-methoxyiminomethyl-pyridine##STR37##

3.3 ml (3.3 mmol) of 1 M tetrabutylammonium fluoride solution intetrahydrofuran is added to a solution of 1.5 g (3.3 mmol) of thecompound from Example 1 in 15 ml of absolute tetrahydrofuran and themixture is stirred at room temperature for 1 hour Saturated sodiumhydrogencarbonate solution is then added to the reaction solution and itis extracted several times with methylene chloride. The combined organicphases are dried (MgSO₄), concentrated and then filtered through silicagel.

Yield: 1.07 g of crude product (94.3% of theory).

¹ H NMR (CDCl₃) δ=1.22 (d, 3H); 1.27 (d, 3H); 3.38 (sept., 1H); 3.48(sept., 1H); 3.72 (s, 3H); 4.33 (d, 2H) 7.0-7.2 (m, 4H); 7.65 (s, 1H)ppm.

Example 32,6-Diisopropyl-4-(4-fluorophenyl)-5-methoxyiminomethylpyridine-3-carbaldehyde##STR38##

0.62 g (6.2 mmol) of neutral alumina and 1.3 g (6.1 mmol) of pyridiniumchlorochromate are added to a solution of 1.05 g (3.05 mmol) of thecompound from Example 2 in 50 ml of methylene chloride and the mixtureis stirred at room temperature for 1 hour. It is filtered throughkieselguhr and then washed with 200 ml of methylene chloride. Themethylene chloride phase is concentrated in vacuo and the residue ischromatographed on a column (100 g of silica gel, 70-230 mesh, diameter3.5 cm) using ethyl acetate/petroleum ether 1:9.

Yield: 830 mg (79.6% of theory).

¹ H NMR (CDCl₃): δ=1.32 (d, 6H); 3.63 (sept., 1H); 3.84 (sept., 1H);3.86 (s, 3H); 7.1-7.3 (m, 4H); 7.78 (s, 1H), 9.79 (s, 1H) ppm.

Example 4(E)-3-[2,6-diisopropyl-4-(4-fluorophenyl)-5-methoxyiminomethyl-pyrid-3-yl]-prop-2-enal##STR39##

750 mg (2.9 mmol) of diethyl 2-(cyclohexylamino)vinylphosphonate,dissolved in 30 ml of dried tetrahydrofuran, are added dropwise at -5°C. under nitrogen to a suspension of 110 mg (3.6 mmol) of 80% puresodium hydride in 15 ml of dry tetrahydrofuran. After 30 minutes, 810 mg(2.4 mmol) of the compound from Example 3 in 40 ml of drytetrahydrofuran are added dropwise at the same temperature and themixture is heated to reflux for 30 minutes. After cooling to roomtemperature, the mixture is added to 200 ml of ice-cold water andextracted three times with 100 ml of ethyl acetate each time. Thecombined organic phases are washed with saturated sodium chloridesolution and dried over magnesium sulphate. After concentrating invacuo, the residue is taken up in 70 ml of toluene, a solution of 4.5 g(3.5 mmol) of oxalic acid dihydrate in 30 ml of water is added and themixture is heated to reflux for 30 minutes.

After cooling to room temperature, the phases are separated, and theorganic phase is washed with saturated sodium chloride solution, driedover magnesium sulphate and concentrated in vacuo. The residue ischromatographed on a column (100 g of silica gel, 70-230 mesh, diameter3.5 cm) using ethyl acetate/petroleum ether 1:9.

Yield 430 mg (48.7% of theory).

¹ H NMR (CDCl₃): δ=1.32 (d, 6H); 3.32 (sept., 1H); 3.61 (sept., 1H);3.83 (s, 3H); 6.03 (dd, 1H); 7.0-7.2 (m, 4H); 7.28 (d, 1H); 7.77 (s, 1H)ppm.

Example 5 Methyl(E)-7-[2,6-diisopropyl-4-(4-fluorophenyl)-5-methoxyiminomethyl-pyrid-3-yl]-5-hydroxy-3-oxo-hept-6-enoate##STR40##

0.18 ml (1.65 mmol) of methyl acetoacetate in 5 ml of drytetrahydrofuran are added dropwise at -5° C. under nitrogen to asuspension of 67 mg (2.2 mmol) of 80% pure sodium hydride in 10 ml ofdry tetrahydrofuran. After 15 min, 1.01 ml (1.65 mmol) of 15% strengthbutyllithium in n-hexane are added dropwise at the same temperature andthe mixture is then stirred for 15 minutes. 410 mg (1.1 mmol) of thecompound from Example 4, dissolved in 10 ml of dry tetrahydrofuran, arethen added and the mixture is stirred at -5° C. for 30 minutes. 0.3 mlof glacial acetic acid is cautiously added to the reaction solution, itis diluted with 100 ml of water and the mixture is extracted 3 timeswith 100 ml of ether each time. The combined organic phases are washedtwice with saturated sodium hydrogencarbonate solution, dried overmagnesium sulphate and concentrated in vacuo. The residue is filteredthrough silica gel (solvent: ethyl acetate/ petroleum ether 1:1).

Yield: 490 mg (91.6% of theory). ¹ H NMR (CDCl₃): δ=1.25 (m, 6H); 2.47(m, 2H); 3.29 (sept., 1H); 3.42 (s, 2H); 3.58 (sept., 1H); 3.75 (s, 3H);3.82 (s, 3H); 4.51 (m, 1H) 5.38 (dd, 1H); 6.36 (d, 1H); 7.0-7.2 (m, 4H);7.77 (s, 1H) ppm.

Example 6 Methylerythro-(E)-7-[2,6-diisopropyl-4-(4-fluorophenyl)-5-methoxyiminomethyl-pyrid-3-yl]-3,5-dihydroxy-hept-6-enoate##STR41##

1.2 ml (1.2 mmol) of 1 M triethylborane solution in tetrahydrofuran areadded at room temperature to a solution of 470 mg (1 mmol) of thecompound from Example 5 in 10 ml of dry tetrahydrofuran, air is passedthrough the solution for 5 minutes and the mixture is cooled to aninternal temperature of -30° C. 46 mg (1.2 mmol) of sodium borohydrideand, slowly, 0.8 ml of methanol are added, the mixture is stirred at-30° C. for 30 minutes and a mixture of 3 ml of 30% strength hydrogenperoxide and 10 ml of water is then added. The temperature is allowed torise to 0° C. during the course of this and the mixture is then stirredfor a further 30 minutes. The mixture is extracted three times with 70ml of ethyl acetate each time, and the combined organic phases arewashed once each with saturated sodium hydrogencarbonate solution andsaturated sodium chloride solution, dried over magnesium sulphate andconcentrated in vacuo. The residue is chromatographed on a column (80 gof silica gel 230-400 mesh, diameter 2.5 cm, with ethylacetate/petroleum ether 1:1).

Yield: 200 mg (41.1% of theory).

¹ H NMR (CDCl₃): δ=1.25 (m, 12H); 1.43 (m, 2H); 2.42 (m, 2H); 3.32(sept., 1H); 3.58 (m, 1H); 3.73 (s, 3H); 3.81 (s, 3H); 4.08 (m, 1H);4.32 (m, 1H); 5.28 (dd, 1H); 6.33 (d, 1H]; 7.0-7.1 (m, 4H); 7.77 (s, 1H)ppm.

Example 7 Sodiumerythro-(E)-7-[2,6-diisopropyl-4-(4-fluorophenyl)-5-methoxyiminomethyl-pyrid-3-yl]-3,5-dihydroxy-hept-6-enoate##STR42##

150 mg (0.3 mmol) of the compound from Example 6 are dissolved in 10 mlof tetrahydrofuran and 3 ml of 0.1 N sodium hydroxide solution areadded. After 1 hour, the tetrahydrofuran is stripped off in vacuo andthe aqueous residue is freeze-dried.

Yield: 143 mg (97% of theory).

¹ H NMR (CDCl₃): δ=0.89 (m, 1H); 1.22 (m, 12H); 1 32 (m, 1H); 1.27 (dd,1H); 1.95 (dd, 1H); 3.31 (s, 3H); 3.38 (sept., 1H); 3.52 (sept., 1H);4.03 (m, 1H); 4.92 (m, 1H) 5.31 (dd, 1H); 6.18 (d, 1H); 7.0-7.3 (m, 4H);7.78 (s, 1H) ppm.

Example 8Trans-(E)-6-[2-(2,6-diisopropyl-4-(4-fluorophenyl)-3-methoxyiminomethyl-pyrid-5-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one ##STR43##

40 mg (0 08 mmol) of the compound from Example 6 are dissolved in 10 mlof tetrahydrofuran and, after addition of 0.8 ml (0.08 mmol) of 0.1 Nsodium hydroxide solution, the mixture is stirred at room temperaturefor 1 hour. It is then diluted with 10 ml of water, adjusted to pH 4.4with 1 N hydrochloric acid and extracted several times with methylenechloride The combined organic phases are dried with sodium sulphate andconcentrated in vacuo. The residue is dissolved in 20 ml of absolutetoluene and, after addition of 5 g of molecular sieve 4 Å, the solutionis heated under reflux overnight. Molecular sieve is then filtered off,and the filtrate is concentrated and filtered through a short silica gelcolumn (eluent ethyl acetate/petroleum ether 1:1).

Yield: 21.1 mg (58.1% of theory).

¹ H NMR (CDCl₃): δ=1.28 (m, 12H); 1.4-1.9 (m, 2H); 2.6 (m, 2H): 3.31(sept., 1H); 3.57 (sept., 1H); 3.82 (s, 3H); 4.18 (m, 1H); 5.08 (m, 1H)5.32 (dd, 1H); 6.42 (d, 1H); 7.0-7.2 (m, 4H); 7.77 (s, 1H) ppm.

Example 93-Benzyloxyiminomethyl-5-tert.-butyldimethylsilyloxymethyl-2,6-diisopropyl-4-(4-fluorophenyl)-pyridine##STR44##

The title compound is obtained from 2.1 g (5 mmol) of the compound fromExample VII and 922.5 mg (7.5 mmol) of benzylhydroxylamine hydrochlorideanalogously to Example 1.

Yield 1.55 g (57% of theory).

¹ H NMR (CDCl₃): δ=0.01 (s, 6H); 0.91 (s, 9H); 1.28 (d, 6H); 1.39 (d,6H); 3.50 (m, 2H); 4.37 (s, 2H); 5.13 (s, 2H); 7.0-7.5 (m, 9H); 7.87 (s,1H) ppm.

Example 10 Methylerythro-(E)-7-[5-benzyloxyiminomethyl-2,6-diisopropyl-4-(4-fluorophenyl)-pyrid-3-yl]-3,5-dihydroxy-hept-6-enoate##STR45##

Example 10 is prepared from the compound of Example 9, in analogy to thereactions of Examples 2-6. ¹ H NMR (CDCl₃) δ=1.26 (m, 12H); 1.42 (m,2H); 2.43 (m, 2H); 3.31 (sept., 1H); 3.44 (sept., 1H); 3.72 (s, 3H);4.08 (m, 1H); 4.30 (m, 1H); 5.05 (s, 2H); 5.26 (dd, 1H); 6 30 (d, 1H);6.98 (m, 4H); 7.2-7.4 (m, 5H); 7.82 (s, 1H) ppm.

Example 113-tert.-Butoxyiminomethyl-5-tert.-butyldimethylsilyloxymethyl-2,6-diisopropyl-4-(4-fluorophenyl)-pyridine##STR46##

The title compound is obtained from 2.1 g

(5 mmol) of the compound from Example VII and 941 mg (7.5 mmol) ofo-tert.-butylhydroxylamine hydrochloride analogously to Example 1.

Yield 770 mg {30.8% of theory).

¹ H NMR (CDCl₃): δ=0.0 (s, 6H); 0.89 (s, 9H); 1.28 (s, 9H); 1.40 (m,6H); 3.48 (sept., 1H); 3.63 (sept., 1H); 4.37 (s, 2H); 7.1-7.3 (m, 4H);7.82 (s, 1H) ppm.

Example 12 Methylerythro-{E)-7-[5-tert.-butyloxyiminomethyl-2,6-diisopropyl-4-(4-f]uorophenyl]-pyrid-3-yl]-3,5-dihyiroxyhept-6-enoate##STR47##

Example 12 was prepared from the compound of Example 11, in analogy tothe reactions of Examples 2-6. ¹ H NMR (CDCl₃): δ=1.1-1.3 (m, 21H); 1.42(m, 2H); 2.42 (m, 2H); 3.32 (sept., 1H); 3.53 (sept., 1H); 3.73 (s, 3H);4.08 (m, 1H); 4.30 (m, 1H); 5.28 (dd, 1H) 6.31 (d, 1H); 7.0-7.1 (m, 4H);7.78 (s, 1H) ppm.

It is understood that the specification and examples are illustrativebut not limitative of the present invention and that other embodimentswithin the spirit and scope of the invention will suggest themselves tothose skilled in the art.

We claim:
 1. A ketone of the formula ##STR48## in which R¹ representsaryl having 6 to 10 carbon atoms, which is optionally monosubstituted totrisubstituted by identical or different substituents from the groupconsisting of halogen, hydroxyl, trifluoromethyl, trifluoromethoxy,nitro, cyano, straight-chain or branched alkyl or alkoxy in each casehaving up to 8 carbon atoms and aryloxy having 6 to 10 carbon atoms,R²represents aryl having 6 to 10 carbon atoms, which is optionallymonosubstituted to trisubstituted by identical or different substituentsfrom the group consisting of straight-chain or branched alkyl in eachcase having up to 8 carbon atoms, halogen, cyano, trifluoromethyl,trifluoromethoxy and nitro, or represents straight-chain or branchedalkyl having up to 10 carbon atoms, which is optionally substituted byaryl having 6 to 10 carbon atoms, hydroxyl or alkoxy having up to 8carbon atoms, or represents a group of the formula --OR⁵, in whichR⁵denotes hydrogen or straight-chain or branched alkyl having up to 8carbon atoms, which is optionally substituted by aryl having 6 to 10carbon atoms, or denotes aryl having 6 to 10 carbon atoms, which isoptionally substituted by straight-chain or branched alkyl or alkoxy ineach case having up to 8 carbon atoms, halogen, nitro, cyano,trifluoromethyl or trifluoromethoxy, R³ and R⁴ are each isopropyl and R⁸represents alkyl.
 2. A compound of the formula ##STR49## in which R¹represents aryl having 6 to 10 carbon atoms, which is optionallymonosubstituted to trisubstituted by identical or different substituentsform the group consisting of halogen, hydroxyl, trifluoromethyl,trifluoromethoxy, nitro, cyano, straight-chain or branched alkyl oralkoxy in each case having up to 8 carbon atoms and aryloxy having 6 to10 carbon atoms,R² represents aryl having 6 to 10 carbon atoms, which isoptionally monosubstituted to trisubstituted by identical or differentsubstituents from the group consisting of straight-chain or branchedalkyl in each case having up to 8 carbon atoms, halogen, cyano,trifluoromethyl, trifluoromethoxy and nitro, or representsstraight-chain or branched alkyl having up to 10 carbon atoms, which isoptionally substituted by aryl having 6 to 10 carbon atoms, hydroxyl oralkoxy having up to 8 carbon atoms, or represents a group of the formula--OR³, in whichR⁵ denotes hydrogen or straight-chain or branched alkylhaving up to 8 carbon atoms, which is optionally substituted by arylhaving 6 to 10 carbon atoms, or denotes aryl having 6 to 10 carbonatoms, which is optionally substituted by straight-chain or branchedalkyl or alkoxy in each case having up to 8 carbon atoms, halogen,nitro, cyano, trifluoromethyl or trifluoromethoxy, R³ and R⁴ are eachisopropyl and R⁹ represents a hydroxyl protecting group.